Prostate cancer (PCA) is a leading cause of cancer-related death in American men. Like other cancers, it develops in the background of diverse genetic and environmental factors. Multiple complex molecular events characterize prostate cancer initiation, unregulated growth, invasion, and metastasis. Distinct sets of genes and proteins dictate progression from precursor lesion, to localized disease and finally to metastic disease. While effective surgical and radiation treatments exist for clinically localized PCA, hormone-refractory metastatic PCA remains essentially, incurable and most men diagnosed with metastatic disease will succumb over a period of months to years. Characterizing genes that regulate the growth of metastatic PCA may offer novel targets for therapeutic intervention. Using DNA microarrays we recently identified EZH2 (enhancer of Zeste homolog 2), a polycomb group protein (PcG), as being up-regulated in metastatic prostate cancer. In Drosophila, PcG proteins have been shown to maintain gene expression programs during development by negatively regulating target loci including homeotic genes. Mis-expression of PcG proteins can lead to defects in proliferation and tumorigenesis. The role of EZH2 and other PcG proteins in prostate cancer has not been investigated. Our long-term goal is to functionally characterize genes identified in our prostate cancer profiling studies. The objective of this application is to begin to study the role of EZH2 in the development of prostate cancer. Our central hypothesis is that dysregulated expression of the PcG protein EZH2 promotes the growth of prostate cancer by transcriptional silencing of specific target genes. Given this, the specific aims of this project will be as follows: Specific Aim 1: Determine the role of EZH2 in regulating prostate cancer growth and development. Specific Aim 2: Confirm that EZH2 functions as a specific transcriptional repressor in prostate cells. Specific Aim 3: Determine expression patterns and clinical associations of PcG proteins in prostate cancer. [unreadable] [unreadable] In summary, this proposal addresses the expression and functional role of EZH2 and related PeG proteins in the growth regulation of prostate cancer. Our ultimate hope is that the functional characterization of EZH2 in metastatic prostate cancer will one day lead to an effective therapy for this invariably lethal disease.